The present invention is directed to compounds of the formula I 
and pharmaceutically acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings:
R1 is lower alkyl, aryl or arylalkyl;
A is hydrogen or 
B is hydrogen, alkyl, alkenyl, or 
but when A is hydrogen, B may only be 
R2, R2xe2x80x2, R2xe2x80x3, R3, R3xe2x80x2 and R3xe2x80x3 are independently hydrogen, hydroxy, alkoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, aryloxy, arylalkoxy, hydroxyalkoxy, lower alkyl, trifluoromethyl, halogen, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, xe2x80x94(CH2)nNR4COR5, xe2x80x94CONR4R4xe2x80x2, xe2x80x94CO2R5, xe2x80x94NR4SO2R1, xe2x80x94NR4R4xe2x80x2, xe2x80x94OCH2CH2NR4R4xe2x80x2, xe2x80x94OCH2CONR4R4xe2x80x2, xe2x80x94OCH2CO2R4, xe2x80x94PO3R4R4xe2x80x2 or aryl; or R2 and R2xe2x80x2 or R3 and R3xe2x80x2 may together form a carbocycle or heterocycle;
m is 0xe2x88x923;
n=0xe2x88x923;
R4 and R4xe2x80x2 are independently hydrogen or lower alkyl; and
R5 is lower alkyl.
The compounds of formula I possess activity at the beta 3 adrenergic receptor in mammals and are useful in the treatment of diabetes, obesity, depression, achalasia and intestinal hypermotility disorders.
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The term xe2x80x9calkylxe2x80x9d refers to both straight and branched chain groups having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl. The term xe2x80x9calkylxe2x80x9d also includes cycloalkyl groups having 1 to 12 carbon atoms, such as cyclopentyl and cyclohexyl.
The term xe2x80x9clower alkylxe2x80x9d as employed herein includes such alkyl groups as described above containing 1 to 6 carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d refers to any of the above alkyl groups linked to an oxygen atom.
The term xe2x80x9clower alkoxyxe2x80x9d refers to any of the above lower alkyl groups linked to an oxygen atom.
The term xe2x80x9calkenylxe2x80x9d refers to monounsaturated straight and branched chain groups having 1 to 12 carbon atoms, such as ethenyl, allyl, 3-butenyl, or 2-methylallyl where the point of attachment may be at a saturated or unsaturated carbon atom.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substituent on either the phenyl or naphthyl may be 1, 2 or 3 lower alkyl groups, halogens or lower alkoxy groups. Phenyl and substituted phenyl are preferred.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to chlorine, bromine, fluorine or iodine.
The term xe2x80x9ccarbocyclexe2x80x9d refers to fully saturated or unsaturated rings of five or six carbon atoms, such as cyclopentane, cyclohexene or benzene.
The term xe2x80x9cheterocyclexe2x80x9d refers to fully saturated or unsaturated rings of five to fifteen atoms containing one to five oxygen and/or sulfur atoms and/or one to four nitrogen atoms provided that the total number of hetero atoms in the ring is five or less.
The compounds of formula I can be converted to salts, in particular pharmaceutically acceptable salts using art recognized procedures. The compounds of formula I have at least one basic center, and they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids for example sulfuric acid, phosphoric acid or a hydrohalic acid, or with organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as alkane- (of 1 to 4 carbon atoms) or arylsulfonic acids, for example methane- or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of formula I having at least one acid group (for example COOH) can form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
It should be understood that the present invention includes prodrug forms of the compounds of formula I.
The compounds of the instant invention may be in the free or hydrate form, and may be obtained by methods exemplified by the following descriptions.
Compounds of formula I can be prepared by reduction of a compound of formula II (which is a novel intermediate) 
with a reducing agent such as borane or lithium aluminum hydride in a solvent such as tetrahydrofuran at a temperature of 0xc2x0 to 65xc2x0 C.
Compounds of formula II can be prepared by coupling compounds of formula III 
with compounds of formula IV 
using standard protocols for amide bond formation, such as stirring at a temperature of 0xc2x0 to 65xc2x0 C. a 1:1 mixture of compounds of formulae III and IV in a solvent such as N,N-dimethylformamide to which is added a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a catalyst such as 1-hydroxy-7-azabenzotriazole or 1-hydroxybenzotriazole hydrate.
The compounds of formula IV are commercially available or are prepared by the methods described in U.S. patent application Ser. No. 08/346,543 filed Dec. 2, 1994, PCT Application WO 95/29159 and EP 611003, Wu and Pridgen, J. Org. Chem. 1991, 56, 1340-1344, and Pridgen Advances in Asymmetric Synthesis, Vol. 2, pp. 55-117 (1997).
Compounds of formula III can be prepared by sulfonylation of the compound of formula V 
with a sulfonylating agent such as methanesulfonyl chloride in a solvent such as pyridine at a temperature of xe2x88x9230xc2x0 to 30xc2x0 C.
The compound of formula V can be prepared by reduction of the compound of formula VI 
with hydrogen gas at a pressure of one to six atmospheres in an alcohol solvent such as methanol or ethanol containing a catalyst such as 10% palladium on carbon. The compound of formula V is susceptible to air oxidation, should be protected from atmospheric oxygen, and should not be purified prior to conversion to the compound of formula III.
The compound of formula VI can be prepared by diazotization of the commercially available compound of formula VII 
by treatment at about 0xc2x0 in a solvent such as water with a nitrite such as sodium nitrite and a strong mineral acid such as sulfuric acid.
Compounds of formula I having S hydroxyl stereochemistry are prepared from the compound of formula VII that is 3-nitro-L-tyrosine.
For compounds of formula I having R hydroxyl stereochemistry the compound of formula VII required is 3-nitro-D-tyrosine.
The above method for the preparation of compounds of formula I from compounds of formula II through VII is the preferred method of preparation. Other methods of preparation of the compounds of formula I are depicted in the context of Examples below.
It is understood that in order to incorporate certain substituents, protecting groups or functional group manipulations may be used by those skilled in the art. These techniques are described in Protective Groups In Organic Synthesis by T. W. Greene and in the series Compendium Of Organic Synthetic Methods, both published by John Wiley and Sons. For example, in cases where R2 is a hydroxyl group, that hydroxyl group may be protected, for example as a benzyl ether, until the last step when it may be deprotected, for example by catalytic hydrogenation. In cases where R2 is a cyano group, that cyano group may be derived from a methoxycarbonyl group by conversion to an aminocarbonyl group by standard methods, followed by dehydration with for example Burgess Reagent ((methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt). In cases where a carboxyl group is present in R2, that carboxyl group may be derived from a methoxycarbonyl group by hydrolysis by standard methods. These strategies for incorporation of substituents apply equally to cases where the substituent is, or is included in, R2xe2x80x2 , R2xe2x80x3 , R3, R3xe2x80x2 and R3xe2x80x3.
The preferred compounds I of the invention are those where R1 is alkyl, m=1, where the hydroxyl stereocenter has the S configuration, and the amino stereocenter has the R configuration, and where A and B are respectively 
Most preferred are compounds I of the invention where R1 is CH3, R2 and R2xe2x80x2 are each CH3O (preferably meta and para), R3, R3xe2x80x2 and R3xe2x80x3 are each H.
It has been found that the preferred beta 3 agonist activity (with minimal beta 1 and beta 2 agonist activity) of the compounds of the invention is associated with the diasteromer where the hydroxyl stereocenter has the S configuration and the amino stereocenter has the R configuration. However, compounds of the invention with other stereochemistries will have the required beta 3 activity as well.
The present compounds of formula I have activity at the beta 3 adrenergic receptor and are therefore useful, for example, in the treatment of diabetes, obesity, gastrointestinal diseases (such as inflammatory bowel disease, irritable bowel syndrome, nonspecific diarrhea, and peptic ulcer), achalasia as well as depression.
Thus a composition containing one (or a combination) of the compounds of this invention, may be administered to a species of mammal (e.g., humans) suffering from diabetes, obesity, an intestinal hypermotility disorder or achalasia or depression as treatment therefor.
A single dose, or two to four divided daily doses, provided on a basis of about 0.1 to 100 mg per kilogram of body weight per day, preferably about l to 15 mg per kilogram of body weight per day is appropriate. The substance is preferably administered orally, but intranasal, transdermal and parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be employed.
The compounds of this invention can also be formulated in combination with beta 1/beta 2 adrenergic blockers such as propranolol and nadolol or stimulants such as salbutamol.
The compounds of formula I can be formulated for use in compositions such as tablets, capsules or elixirs for oral administration, in sterile solutions or suspensions for parenteral or intranasal administration, buccal patches, or in transdermal patches, with transdermal patches being preferred. About 10 to 500 mg of a compound of formula I is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Based on the literature, it is expected that these compounds may be useful for other indications such as treatment of stress, regulation of intraocular pressure, treatment of conditions associated with increased protein breakdown such as during convalescence after surgery, treatment of triglyceridemia, hypercholesterolemia, atherosclerotic and cardiovascular diseases, and increasing high density lipoprotein levels. In addition, it is expected that these compounds may be useful as feed additives for fattening or improving weight gain or increasing lean body mass in animals and may therefore be used to decrease birth mortality and increase post-natal survival rates in animals.
In addition, based on the literature, compounds of formula I are expected to be useful for improving healing and preventing stomach ulcers (K. Kuratani et. al., J. Pharmacol. Exp. Ther., 270, 559 (1994)). The compounds of formula I are also expected to be useful for regulating core temperature.
The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto.
The following Examples represent preferred embodiments of the present invention.